Means for treating prostate hypertrophy and prostate cancer

ABSTRACT

A regime for therapeutic management of a benign prostatic hyperplasia and prostatic cancer employs Cetrorelix alone or in combination with α-reductase inhibitors or α-receptor blocking agents. The regiment reduces the volume of the prostate and avoids the side effects associated with testosterone levels being in a castration range. Cetrorelix is administered at dosages between 0.5 mg/day and 20 mg/week or about 0.014 mg/kg body weight per day to 0.30 mg/kg body weight per week or at levels of about 25 to 120 mg of Cetrorelix per month or 0.376 mg/kg to 1.71 mg/kg per month. Cetrorelix can be administered with α-reductase inhibitors or a α-receptor blocking agents.

This application is a division of Ser. No. 09/057,458 filed Apr. 9,1998, now U.S. Pat. No. 5,998,377 which is a continuation of Provisionalapplication Nos. 60/025,990 filed Sep. 12, 1996 and 60/043,228 filedApr. 10, 1997

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is related to a method of treating benign prostatehypertrophy (BPH) and prostate cancer as well as to means of usetherefor.

2. Description of Related Art

BPH is a disease conditioned by age and affects approximately 60% of allmen older than 60. Pathogenetically, an elevated accumulation ofdihydrotestosterone in the prostate tissue is assumed to causeenlargement of the prostate. The accumulation of dihydrotestosterone isthought to be the result of elevated intracellular bonding based onreceptor increase. The increase in receptors is stimulated by theelevation of the estrogen levels relative to androgen levels whichdecrease with age. The urological symptoms consist in an elevatedfrequency of miction due to elevated residual urine, which bothers thepatients especially during the night hours. This is accompanied by aweak flow of urine, a time-delayed start of miction, and repeatedinfections of the bladder and kidneys.

Surgical elimination of the obstruction due to prostate enlargement isstill considered the “gold standard” within the various modalities oftreatment. Surgery, however, is not effective for all patients. Openoperation or a transurethral resection results in no improvement inapproximately 10 to 15% of the patients due to the presence of othercauses, e.g. neurogenic bladder, infections. In addition, these invasivemethods entail additional risks such as the occurrence of a retrogradeejaculation, diminished libido arid urine incontinence. Less invasivemethods exist, e.g. balloon dilatation and treatment with hyperthermiaor microwaves.

It has been established that an androgen-ablative therapy can yieldpositive results in the case of BPH; however, it is unclear whether fullsuppression should. be achieved. The standard therapy for testosteronesuppression in the case of prostate carcinomas consists in a bilateralorchiectomy. This is not generally acceptable for a benign sickness suchas BPH. Another possibility involves influencing the effects of thesexual steroids through the use of LHRH analogues (LHRH=luteinizinghormone-releasing hormone)

After an initial stimulation of the steroid, the use of “superagonists”causes suppression of testosterone at castration levels. The stimulationis due to their mechanism of action. Unfortunately, the use of“superagonists” has the same undesirable side effects associated withsurgical castration.

Dyssynergia α-receptor blockers can be used in the case of a rigidsphincter or bladder sphincter. Alternative drug regimens involve theuse of 5-α-reductase inhibitors such as Finasteride to inhibit theformation of dihydrotestosterone. This regimen has the additionaladvantage of not negatively influencing the libido or potency.

EP 0.401,653 teaches the use of Naftopidil for therapy of dysuria in BPH(oral daily 10-100 mg). Dysuria is discussed in the background section.

WO publication 91/100731 describes a combination therapy for theprophylaxis or treatment of BPH by the combined administration of 2 ormore therapeutic substances. The substances are selected from the groupof 5-α-reductase inhibitors, anti-estrogens, aromatase inhibitors,inhibitors of 17β-hydroxysteroid dehydrogenase activity and, in a fewinstances, of anti-androgens and/or LHRH agonists/antagonists. Theanti-androgens were preferably given 2 to 4 hours before theadministration of the LHRH agonist.

WO publication 91/00733 teaches the treatment of androgen-dependentdiseases with a new anti-androgen which can also be used in the contextof a combination therapy. The treatment includes the steps of inhibitingthe testicular hormonal secretion by administering an antagonist of LHRHor an agonist of LHRH along with a pharmaceutically effective amount ofan anti-androgen.

WO publication 92/16233 describes the combined use of an inhibitor of5-α-reductase and an anti-androgen for the treatment of prostate cancer.The combination of Finasteride with an anti-androgen, e.g. Flutamide, isalso taught. The use of a composition of various LHRH agonists and of ananti-androgen for treating BPH is also suggested by U.S. Pat. No.4,472,382.

WO publication 92/16213 teaches a method of treating BPH byadministering an inhibitor of 5-α-reductase select from 17β-substituted4-azasteroid, 17β-substituted non-azasteroid,17β-acetyl-3-carboxy-androst-3,6-diene together with an α¹ adrenergicreceptor blocker selected from Terazosin, Doxazosin, Prazosin,Bunazosin, Indoramin, Alfuzosin.

The use of the LHRH antagonist Cetrorelix (SB 75), (see also EP 0299402), for treating BPH is suggested in “The Prostate” 24:84 92 (1994),(Gonzalez-Barcena et al). Gonzalez-Barcena et al. report desirableclinical results, e.g. a decrease in prostate volume, after theadministration of 500 μg Cetrorelix (SB-075) every 12 hours for 4 weeksto BPH patients. Prostate carcinoma patients were also similarly treatedfor 6 weeks. In all patients, there was initially a lowering intestosterone levels to a castration level. In the BPH patients, thetestosterone levels fluctuated at subnormal levels. None of the patientshad testosterone levels which reached castration values during the lastthree weeks of the treatment. There was a distinct decrease of thesymptoms of dysuria and also the prostate volume. In the prostatecarcinoma patients, the testosterone values were measured again at: thecastration levels at the end of the 6 weeks of therapy along with aconsiderable improvement in the overall condition of the patient.

The potential suitability of LHRH antagonists, including Cetrorelix, fortreating BPH appears in a review article appearing in Arch.-Pharmakol.350, Suppl., R16, 1994 (Romeis, Ochs, Borbe). In vitro bonding ofCetrorelix to LHRH receptors on the pituitary gland of swine ismentioned. Also mentioned are other possible clinical areas ofapplication, including hormone-dependent tumors.

A comparative survey of the endocrine therapy of BPH in conjunction with5-α-reductase inhibitors, aromatase inhibitors and anti-androgens ispresented in Urology, 1994, 43, 22 suppl. (7-16). However, only LHRHagonists are described.

An overriding disadvantage of known preparations and methods is that thepatient usually experiences a sharp drop in testosterone levels alongwith its associated side effects. In addition, known preparations haveonly a relatively short term effect. The prostate volume rises onceadministration stops. An effective therapy scheme for the treatment ofBPH with Cetrorelix has not been established.

SUMMARY OF THE INVENTION

The disclosed invention is directed to a long-lasting therapeutic agenthaving few side effects for the treatment of both BPH and prostatecancer.

The problems existing with the treatments described above are solved byadministering the LHRH antagonist Cetrorelix alone or in combinationwith α-blockers or 5-α-reductase inhibitors such as Finasterides.Preferably, Cetrorelix was administered intermittently according to aspecified therapy scheme.

It is also possible with the LHRH antagonist Cetrorelix to determine theextent of a testosterone suppression via the level of the applied doseand also to compensate for it.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a summary of the clinical results for specific Cetrorelixdosage regimens. PLA refers to a placebo;

FIG. 2(a) shows the effect of the C01 and C10 treatments on prostatesize. PLA refers to a placebo;

TREATMENTS C01 refers to a dosage regimen of 1 mg/day s.c. for 28 daysand a 3 months follow-up observation period. C10 refers to a dosageregimen of 10 mg/day for the first one to five days followed by a dosageregime of 1 mg/day s.c. for 28 days and a 3 months follow-up observationperiod.

FIG. 2(b) illustrates the absolute changes in prostate size frombaseline for the C01 and C10,

FIG. 3(a) shows the number of patients with an I-PSS improvement ≧40%and also with an improvement ≧30% resulting from the treatment C01 andC10 (defined above). PLA is the placebo. I-PSS (International ProstateSymptom Score) includes the following indicia of 1) feeling ofincomplete voiding, 2) increased frequency of voiding, 3) dribbling, 4)difficulties to postpone voiding 5) weak urinary stream 6) increasedeffort to start voiding and 7) nycturia;

FIG. 3(b) shows the I-PSS improvement with the C10 and C01 treatments(defined above) over 120 days, including the observational follow-upperiod.

FIG. 4(a) shows the improvement in maximum uroflow ≧3 ml/sec C10 and C01(defined above) treatment phases. PLA is the placebo, and

FIG. 4(b) shows the rate of uroflow as a function of the C01 and C10treatments (defined above) over a 120 day period.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will be explained in detail using the following clinicalresults:

EXAMPLES Example 1

Cetrorelix is administered in a dose of 0.5 mg to 2 mg daily for 4 to 8weeks for the therapy of BPH. A dose of 5 mg to 30 mg, dispensed onceper week or every 10 days also over a time period of 4 to 8 weeks aswell as one every two weeks or one injection per month of 20 mg to 60 mgcan also decisively improve the clinical symptoms and signs. Submaximaldecreases of testosterone occur, but these are above those levelsassociated with castration. The prostate volume decreases by 20 to 40%during the treatment time of 4 to 8 weeks. An increase of the peak flowof approximately 3 ml/sec of the urine, comparable to the α-blockers, isalso achieved with this therapy regimen. In addition, at least 30% ofthe patients achieve an improvement of the urine flow of 6 ml/sec withthis therapy. This is almost equivalent to an improvement like thatassociated with the golden standard operation, and in considerablyshorter time. No limitations in sexual performance are observed. Thereare also significant improvements as regards quality of life. Theseclinical benefits continue for at least 3 to 6 months after therapy.This allows a long-term therapy of BPH with only an intermittenttreatment of 2 to max. 4 injection cycles over 4 to 8 weeks.

This therapy represents a significant therapeutic advance in thetreatment of BPH since it not only achieves an improvement of theclinical symptoms of BPH but also a diminution of the prostate and animprovement of the urine flow like those associated with surgery. Theprotocols of the invention avoid the negative consequences of anoperation, e.g. urine incontinence, retrograde ejaculation, blood losswith the consequence of blood transfusions and also the risks ofinfection associated with surgery.

Example 2

Cetrorelix is administered with α-reductase inhibitors or α-receptorblocking agents to a patient as followsFor

For 1 to 12 weeks, Cetrorelix is administered to the patient followed bya 1-12 week period where an α-redutase inhibitor of 5 mg/day, anα-receptor blocking agent in the dose range of 2 mg to 10 mg/day or of0.1 mg to 0.4 mg/day dependent on each agent or a drug of natural origin1-6 capsules or tablets/day used for the treatment of BPH isadministered. Alternatively, Cetrorelix can be administered for a 1 to12 weeks period followed by retreatment with Cetrorelix after one to sixmonths.

In summary, it can be readily seen that treatment of BPH with a specifictherapy regime involving Cetrorelix or especially a combination ofCetrorelix with 5-α-reductase inhibitors or α-blockers such asNaftopidil has decided benefits which occur quickly and arelong-lasting.

An effective and economic therapy of this widespread disease can beachieved therewith, which is of extraordinary social and economicsignificance.

We claim:
 1. A regime for therapeutic management of prostatic cancer ina mammalian organism without testosterone levels being in castrationrange comprising the administration of Cetrorelix, an LH-RH antagonist,wherein said LH-RH antagonist is administered over time and in an amountsufficient to reduce the volume of the prostate specific antigen levels,without the side effects associated with testosterone levels being in acastration range.
 2. The regime according to claim 1 wherein Cetrorelixis administered as LH-RH antagonist at a dosage between 0.5 mg/day and20 mg/week or about 0.007 mg/kg body weight per day to 0.30 mg/kg bodyweight per week.
 3. The regime according to claim 1 wherein Cetrorelixis administered as LH-RH antagonist at a dosage between 20 to 120mg/month or about 0.285 mg/kg to 1.171 mg/kg per month for one to sixmonths.
 4. The regime according to claim 1 wherein Cetrorelix isadministered as LH-RH antagonist at a dosage between 20 to 120 mg/monthor about 0.285 mg/kg to 1.171 mg/kg per month for one to three months.5. The regime according to claim 1 comprising administration ofCetrorelix for 1 to 12 weeks followed by retreatment with Cetrorelixafter six months.